Transforming growth factor β signaling inhibitor, SB-431542, induces maturation of dendritic cells and enhances anti-tumor activity

  • Authors:
    • Hiroaki Tanaka
    • Osamu Shinto
    • Masakazu Yashiro
    • Sadaaki Yamazoe
    • Takehiko Iwauchi
    • Kazuya Muguruma
    • Naoshi Kubo
    • Masaichi Ohira
    • Kosei Hirakawa
  • View Affiliations

  • Published online on: December 1, 2010     https://doi.org/10.3892/or_00001028
  • Pages: 1637-1643
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Abstract

The transforming growth factor β (TGFβ) stimulates tumor progression and metastasis. Secretion of TGFβ by tumor cells also suppresses an antitumor immune response in which dendritic cells (DCs) play an important role to activate cytotoxic T lymphocytes (CTLs). Herein we report that the small molecule TGFβ signaling inhibitor SB-431542, induces DC maturation in vitro and triggers antitumor activity in vivo. We added SB-431542 to cultures of murine bone-marrow derived DCs (BM-DCs) derived from BALB/c mice and human DCs generated from peripheral monocytes (human DCs) at different concentrations in triplicates and examined expression of co-stimulatory molecules by FACS and production of Interleukin-12 (IL-12) by ELISA. SB induced phenotypic maturation of BM-DCs and human DCs and improved their abilities to produce IL-12 in a dose-dependent manner. SB-431542 also augmented capacity of murine and human DCs to activate naive T cells in allogeneic mixed lymphocyte reaction. Interestingly, SB-431542 augmented the capacity of BM-DCs and human DCs to incorporate FITC-conjugated dextran. Intraperitoneal administration of SB-431542 intiated 3 and 7 days after the implantation of colon-26 cancer cells into the peritoneal cavity of BALB/c mice significantly induced CTL activity against colon-26. We incubated human DCs with SB-431542 and cell lysate of scirrhous gastric cancer cell line OCUM-8, and then examined CTL activities against OCUM-8. CD8 T cells activated by human DCs treated with SB-431542 showed modest augmentation CTL activity against cancer cells. Furthermore, pretreatment of human DCs with SB-431542 upregulated cytotoxic activity against K562 cells, suggesting SB should have potential to activate DCs to natural killer cells. In conclusion, TGFβ receptor I kinase inhibitor such as SB-431542 might induce anti-tumor immune response in immuno-tolerant patients associated with TGFβ activity.

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December 2010
Volume 24 Issue 6

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Spandidos Publications style
Tanaka H, Shinto O, Yashiro M, Yamazoe S, Iwauchi T, Muguruma K, Kubo N, Ohira M and Hirakawa K: Transforming growth factor β signaling inhibitor, SB-431542, induces maturation of dendritic cells and enhances anti-tumor activity . Oncol Rep 24: 1637-1643, 2010
APA
Tanaka, H., Shinto, O., Yashiro, M., Yamazoe, S., Iwauchi, T., Muguruma, K. ... Hirakawa, K. (2010). Transforming growth factor β signaling inhibitor, SB-431542, induces maturation of dendritic cells and enhances anti-tumor activity . Oncology Reports, 24, 1637-1643. https://doi.org/10.3892/or_00001028
MLA
Tanaka, H., Shinto, O., Yashiro, M., Yamazoe, S., Iwauchi, T., Muguruma, K., Kubo, N., Ohira, M., Hirakawa, K."Transforming growth factor β signaling inhibitor, SB-431542, induces maturation of dendritic cells and enhances anti-tumor activity ". Oncology Reports 24.6 (2010): 1637-1643.
Chicago
Tanaka, H., Shinto, O., Yashiro, M., Yamazoe, S., Iwauchi, T., Muguruma, K., Kubo, N., Ohira, M., Hirakawa, K."Transforming growth factor β signaling inhibitor, SB-431542, induces maturation of dendritic cells and enhances anti-tumor activity ". Oncology Reports 24, no. 6 (2010): 1637-1643. https://doi.org/10.3892/or_00001028